In the last two decades the importance of gasotransmitters in biological processes has been recognized, especially that of nitric oxide (NO) and hydrogen sulfide which have been implicated in a number of bioregulatory processes including normal physiological control of blood pressure, macrophage destruction of foreign pathogens, ischemic reperfusion injury, hemorrhagic shock, platelet aggregation, and neurotransmission. Recent research has further demonstrated that they possess a broad-spectrum of antimicrobial and anti-viral activity and may be used as an alternative to conventional antibiotics for drug resistant bacteria. In addition, gasotransmitters may also be used to alleviate inflammation and promote wound healing.
However, as gases at ambient temperature and atmospheric pressure, with short half-lives in physiological milieu it has proved relatively challenging to deliver gasotransmitters in a controlled and targeted manner. The use of gasotransmitters is further complicated by the time dependent concentration profile that is common in biological systems such as wound healing. In order to utilize gasotransmitters and mimic their bioregulatory function, they must be delivered in a manner that allows the flux (concentration) to be varied in a time dependent manner.
The present disclosure relates generally to gasotransmitter delivery formulations and devices. In the invention disclosed herein, the amount of gasotransmitter that is generated may be controlled in order to have a desired effect in a particular application. As one example, periodic gasotransmitter generation may be used for dispersing biofilm and killing bacteria. As another example, a steady physiologically-relevant flux of gasotransmitter for a predetermined time period may be generated to reduce thrombus formation and prevent infection. As still another example, a variable flux of gasotransmitter can be generated to deliver a physiologically-relevant time dependent concentration profile of gasotransmitter, to assist in wound healing for example.
In the last two decades the importance of gasotransmitters in biological processes has been recognized. It has become apparent that these gaseous signaling molecules are crucially important in a wide range of biological processess1,2,3. Endogenous gasotransmitters with their profound effects on mammalian physiology have, potentially, major implications in therapeutic applications4. The potential of gasotransmitters has been investigated for the nitric oxide5,6,7 and hydrogen sulfide8-10 treatment of neuropathy, tissue11,12, platelet13 and blood preservation14, reperfusion injury13-18, wound healing21-25 and control of bacterial infections26-29. These studies have clearly demonstrated the therapeutic value of gasotransmitters.
To apply gasotransmitters in a clinical setting requires delivery to the situs of action. US20070065473A1 and PCT/US2012/058564 describe the delivery of gaseous nitric oxide as a cosmetic and wound healing agent. This approach has the clear disadvantage that delivery requires sealing the area to be treated. To overcome this issue, the generation of nitric oxide at the situs of action has been attempted. US20110104240A1 describes a method of generating nitric oxide by reduction of nitrite with an enzyme or living cell within a wound dressing. US20150297782 A1 describes the generation of nitric oxide in situ by the reaction of citric acid and nitrite ions within a dressing or article contacting a wound. Another attempt to deliver nitric oxide in a controlled and targeted manner is through acid decomposition of nitrite salts as described by Edixomed in WO/2014/188175A. These approaches deliver nitric oxide from a solid formulation but with limited control over the release profile.
U.S. Pat. No. 6,737,447 B1 uses an alternative approach to the generation of nitric oxide at the site of action. Nitric oxide is delivered bound to a polymer that forms part of the dressing. Release is triggered by exudate from the wound. WO2000030658 A1 describes the delivery of nitric oxide from the natural polymer chitosan. Another approach is described by BASF in US application U.S. Ser. No. 13/975,930 and Novan Inc. US 20140134321 and US 20140171395. While these polymers allow nitric oxide to be delivered as a solid, there is limited control over the release profile.
A further attempt to deliver nitric oxide in a controlled and targeted manner is through electrochemical reduction of nitrite to nitric oxide as described in U.S. Pat. No. 9,480,785. The electrochemical generation of nitric oxide is achieved by generation of copper (I) at an electrode. This approach, like the invention described herein, utilizes electrochemical reduction of nitrite to nitric oxide. In contrast to U.S. Pat. No. 9,480,785 the present invention uses an organic mediator and thus avoids issues with electrode passivation and compatibility with open wounds.
The application of nitric oxide has been relatively limited because of the absence of a controlled and targeted delivery method or material. Therefore, there is a need for a gasotransmitter delivery system, that can deliver these species in a temporally, spatially and targeted manner. Gasotransmitters are endogenously generated molecules of gas.